Double-blind, placebo-controlled trial of risperidone plus topiramate in children with autistic disorder

doi:10.1016/j.pnpbp.2010.07.005

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Volume 34, Issue 7, 1 October 2010, Pages 1269-1272

https://doi.org/10.1016/j.pnpbp.2010.07.005 Get rights and content

Abstract

Background

Autism is a complex neurodevelopmental disorder that forms part of a spectrum of related disorders referred to as Autism Spectrum Disorders. The present study assessed the effects of topiramate plus risperidone in the treatment of autistic disorder.

Method

Forty children between the ages of 4 and 12 years with a DSM IV clinical diagnosis of autism who were outpatients from a specialty clinic for children were recruited. The children presented with a chief complaint of severely disruptive symptoms related to autistic disorder. Patients were randomly allocated to topiramate + risperidone (Group A) or placebo + risperidone (Group B) for an 8-week, double-blind, placebo-controlled study. The dose of risperidone was titrated up to 2 mg/day for children between 10 and 40 kg and 3 mg/day for children weighting above 40 kg. The dose of topiramate was titrated up to 200 mg/day depending on weight (100 mg/day for < 30 kg and 200 mg/day for > 30 kg). Patients were assessed at baseline and after 2, 4, 6 and 8 weeks after starting medication. Measure of outcome was the Aberrant Behavior Checklist-Community (ABC-C) Rating Scale.

Results

Difference between the two protocols was significant as the group that received topiramate had a greater reduction in ABC-C subscale scores for irritability, stereotypic behavior and hyperactivity/noncompliance.

Conclusion

The results suggest that the combination of topiramate with risperidone may be superior to risperidone monotherapy for children with autistic disorder. However the results need to be further confirmed by a larger randomized controlled trial.

Introduction

Autism is a severe, chronic development disorder, involving marked retardation of aptitudes for social interaction, communication and play (Myers, 2007). A meta-analysis of 37 studies of autism prevalence reported from USA, UK, Europe and Japan has estimated that the prevalence of autism is 7.1 per 10,000 in individuals less than 18 years old (Williams et al., 2006). While behavioral therapies are clearly and without question the interventions of choice for those with autism there is also often the need for psychopharmacologic intervention (West et al., 2009). Psychotropic medications are used in children with autism in a predominantly off-label manner in particular for behavioral disturbance (Mohammadi and Akhondzadeh, 2007). One way to indirectly investigate the pathophysiology of autism is to study the effect of a drug that may modulate the release of glutamate or the function of excitatory receptors (Mohammadi and Akhondzadeh, 2007). Medications that prevent excitotoxicity are desirable for treatment of asphyxia, stroke, and may benefit other neurological disorders such as autism (Levy and Hyman, 2005, Leskovec et al., 2008). Recently, there has been rising interest in the use of antiepileptic drugs (AED) in the management of pervasive developmental disorder (PDD) (Tuchman, 2004). Studies examining the effectiveness of AED for the treatment of PDD show some promise (Hellings et al., 2005, Anagnostou et al., 2006).

There are several reasons for the use of antiepileptic drugs in autistic spectrum disorders, including the high incidence of epilepsy in these individuals, the anecdotal reports suggesting an improvement of communication and behavior in autistic subjects with epileptic discharges, and the increased awareness that some disruptive behaviors may be manifestations of an associated affective disorder (Tuchman, 2004). Topiramate is a novel broad-spectrum anticonvulsant with a unique pharmacologic profile; it inhibits glutamate activity at the a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate subtype of glutamate receptors, attenuates activity at Na⁺ channels and high-voltage activated Ca²⁺ channels, and augments effects at gamma-aminobutyric acid (GABA) receptor subtypes (GABA_A) (Shank et al., 2000, Ormrod and McClellan, 2001). Topiramate is tolerated well in children and adolescents with epilepsy (Glauser, 1998) and is indicated for adjunctive treatment of epilepsy in children 2 years of age and older as well as for prevention of migraine headaches in adults (Ferraro and Di Trapani, 2008). Harden et al. in a retrospective study in fifteen patients showed that topiramate may be beneficial for treating secondary symptoms of PDD (Hardan et al., 2004). However, they mentioned that prospective open label studies or double-blind, placebo-controlled studies are needed to assess its efficacy and safety.

We assessed the effects of topiramate plus risperidone in the treatment of autistic disorder in particular for irritability symptoms. From a scientific viewpoint, the therapeutic effects of topiramate without an additional neuroleptic drug would be more interesting. However, since atypical antipsychotics are relatively effective in the treatment of autism, our ethics committees would not approve a study with topiramate as the only drug for autistic patients. To the best of our knowledge, this study is the first double-blind and placebo-controlled clinical trial assessing the adjunctive role of topiramate in the management of autism.

Section snippets

Methods

This was a 8-week, parallel group, placebo-controlled trial undertaken in the children's outpatient clinic of Hafez Hospital, Shiraz University of Medical Sciences, Shiraz, Iran during April 2008–January 2010.

Results

Forty patients were randomized to trial medication. No significant differences were identified between patients randomly assigned to group A (topiramate) or B (placebo) with regard to basic demographic data including age, gender and weight (Table 1). All patients completed the trial and there were no missing data.

Discussion

Autistic disorder is a neurodevelopmental disorder that causes lifelong impairment in socialization, communication, and behavior. Although pharmacologic treatments do not target the core symptoms of autism, many medications are available to ameliorate associated symptoms, which often prove to be the most disturbing in the lives of affected children and their families (Mohammadi and Akhondzadeh, 2007). When considering pharmacologic treatment, it is important to identify the potential target

Acknowledgments

This study was Dr. Vala Rezaei's postgraduate thesis toward the Iranian Board of Psychiatry. This study was supported by a grant from Tehran University of Medical Sciences to Prof. Shahin Akhondzadeh (Grant No: 6550).

References (27)

S. Akhondzadeh et al.
Double-blind placebo-controlled trial of pentoxifylline added to risperidone: effects on aberrant behavior in children with autism
Prog Neuropsychopharmacol Biol Psychiatry
(2010)
L. Mazzone et al.
Topiramate in children with autistic spectrum disorders
Brain Dev
(2006)
H. Niederhofer
Also topiramate might have some benefit in psychopharmacological treatment of autism
Med Hypotheses
(2008)
L. West et al.
Pharmacologic treatment for the core deficits and associated symptoms of autism in children
J Pediatr Health Care
(2009)
S. Akhondzadeh et al.
Cyproheptadine in the treatment of autistic disorder: a double-blind and placebo controlled trial
J Clin Pharm Ther
(2004)
S. Akhondzadeh et al.
A double-blind placebo controlled trial of piracetam added to risperidone in patients with autistic disorder
Child Psychiatry Hum Dev
(2008)
M.G. Aman et al.
The aberrant behavior checklist: a behavior rating scale for assessment of treatment effects
Am J Ment Defic
(1985)
American Psychiatric Association
Diagnostic and statistical manual of mental disorders
(2000)
E. Anagnostou et al.
Divalproex versus placebo for the prevention of irritability associated with fluoxetine treatment in autism spectrum disorder
J Clin Psychopharmacol
(2006)
K.M. Belsito et al.
Lamotrigine therapy for autistic disorder: A randomized, double-blind, placebo controlled trial
J Autism Dev Disord
(2001)

K.N. Chengappa et al.

Topiramate in the management of bipolar disorder

Child Adolesc Psychopharmacol News

(2001)

G. Chouinard et al.

Extrapyramidal symptoms rating scale (abstract)

Can J Neurol Sci

(1980)

J.F. Cubells

Targeting the glutamate system in the treatment of autistic spectrum disorders

Curr Psychiatry Rep

(2007)

Cited by (91)

Psychopharmacology Management in Autism Spectrum Disorder
2024, Pediatric Clinics of North America
Systematic Review and Meta-analysis: Pharmacological and Nonpharmacological Interventions for Persistent Nonepisodic Irritability
2023, Journal of the American Academy of Child and Adolescent Psychiatry
Citation Excerpt :
In total, 101 intervention studies were included in the meta-analysis, comprising 6,953 youth with persistent non-episodic irritability (study sample sizes ranged from 8 to 579; Figure 1 presents the PRISMA flowchart). Descriptions of the 101 articles (42 open trial, 59 RCT) included in this systematic review and meta-analysis can be found in Table 1.28-125 ( Included studies targeted a range of ages, with youth ages 2+ years being represented in the current meta-analysis, suggesting that results from this meta-analysis are representative of the full preschool through adolescent developmental periods.
This meta-analysis examined the efficacy of available pharmacological and nonpharmacological interventions for irritability among youth with autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), disruptive behavior disorders (DBD), disruptive mood dysregulation disorder (DMDD), and/or severe mood dysregulation (SMD).
Literature searches were conducted in October 2020, resulting in 564 abstracts being reviewed to identify relevant papers, with 387 articles being reviewed in full. A random effects model was used for the meta-analysis, with subgroup meta-regressions run to assess effects of study design, intervention type, medication class, and clinical population.
A total of 101 studies were included (80 pharmacological, 13 nonpharmacological, 8 combined). Despite high heterogeneity in effects (I² = 94.3%), pooled posttreatment effect size for decreasing irritability was large (Hedges’ g = 1.62). Large effects were found for pharmacological (g = 1.85) and nonpharmacological (g = 1.11) interventions; moderate effects were found for combined interventions relative to monotherapy interventions (g = 0.69). Antipsychotic medications provided the largest effect for reducing irritability relative to all other medication classes and nonpharmacological interventions. A large effect was found for youth with ASD (g = 1.89), whereas a medium effect was found for youth with ADHD/DMDD/DBD/SMD (g = 0.64).
This meta-analysis provides a comprehensive review of interventions targeting persistent nonepisodic irritability among youth with various psychiatric disorders. Strong evidence was found for medium-to-large effects across study design, intervention type, and clinical populations, with the largest effects for pharmacological interventions, particularly antipsychotic medications and combined pharmacological interventions, and interventions for youth with ASD.
Autism Spectrum Disorder
2022, Comprehensive Pharmacology
Autism spectrum disorder (ASD) is a common neurobehavioral disorder with considerable complexity and without clearly defined etiologic underpinnings. A variety of factors are intertwined in this condition including genetic, biochemical, and cellular characteristics. A major aspect of ASD management is behavioral therapy, though pharmacologic agents produce major benefits as well. This work considers current pharmacologic principles in treatment of ASD in children, adolescents, and adults. Pharmacologic intervention is particularly helpful for treatment of the conditions that are frequently co-morbid with ASD—including anxiety, depression, aggressive/violent behaviors, repetitive behaviors, inattention with hyperactivity, and sleep disorders.
Dendritic spine membrane proteome and its alterations in autistic spectrum disorder
2022, Advances in Protein Chemistry and Structural Biology
Citation Excerpt :
Interestingly, pharmacological modulation of AMPA receptors by antagonists rescue the social impairments in the VPA-induced ASD animal model (Kim et al., 2019). In patients with ASD the therapeutic efficacy of GluR antagonists has also been reported (Doyle & McDougle, 2012; Erickson et al., 2007, 2011, 2013; Rezaei et al., 2010). In support of the contrasting hypo-glutamate hypothesis, several animal models of ASD provide evidence of an altered NMDAR signaling pathway as a result of the downregulation of the principal NMDAR subunit, GluN1 (Uzunova, Hollander, & Shepherd, 2014).
Dendritic spines are small protrusions stemming from the dendritic shaft that constitute the primary specialization for receiving and processing excitatory neurotransmission in brain synapses. The disruption of dendritic spine function in several neurological and neuropsychiatric diseases leads to severe information-processing deficits with impairments in neuronal connectivity and plasticity. Spine dysregulation is usually accompanied by morphological alterations to spine shape, size and/or number that may occur at early pathophysiological stages and not necessarily be reflected in clinical manifestations. Autism spectrum disorder (ASD) is one such group of diseases involving changes in neuronal connectivity and abnormal morphology of dendritic spines on postsynaptic neurons. These alterations at the subcellular level correlate with molecular changes in the spine proteome, with alterations in the copy number, topography, or in severe cases in the phenotype of the molecular components, predominantly of those proteins involved in spine recognition and adhesion, reflected in abnormally short lifetimes of the synapse and compensatory increases in synaptic connections. Since cholinergic neurotransmission participates in the regulation of cognitive function (attention, memory, learning processes, cognitive flexibility, social interactions) brain acetylcholine receptors are likely to play an important role in the dysfunctional synapses in ASD, either directly or indirectly via the modulatory functions exerted on other neurotransmitter receptor proteins and spine-resident proteins.
The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present
2021, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
Second-generation antiepileptics, like lamotrigine and levetiracetam, have been perhaps even more disappointing when prescribed for the control of behavioral symptoms in ASD (Table 4). Instead, positive results have been obtained in add-on protocols, whereby valproic acid was found to blunt fluoxetine-induced irritability (Anagnostou et al., 2006) and topiramate to boost the efficacy of risperidone on irritability, hyperactivity and stereotypic behaviors (Rezaei et al., 2010). This promising add-on approach may pave the path toward a more rational and synergistic use of these drugs.
Autism Spectrum Disorder (ASD) is a severe and lifelong neurodevelopmental disorder, with high social costs and a dramatic burden on the quality of life of patients and family members. Despite its high prevalence, reaching 1/54 children and 1/45 adults in the United States, no pharmacological treatment is still directed to core symptoms of ASD, encompassing social and communication deficits, repetitive behaviors, restricted interests, and abnormal sensory processing. The purpose of this review is to provide an overview of the state-of-the-art of psychopharmacological therapy available today for ASD in children and adolescents, in order to foster best practices and to organize new strategies for future research. To date, atypical antipsychotics such as risperidone and aripiprazole represent the first line of intervention for hyperactivity, impulsivity, agitation, temper outbursts or aggression towards self or others. Tricyclic antidepressants are less prescribed because of uncertain efficacy and important side effects. SSRIs, especially fluoxetine and sertraline, may be effective in treating repetitive behaviors (anxiety and obsessive-compulsive symptoms) and irritability/agitation, while mirtazapine is more helpful with sleep problems. Low doses of buspirone have shown some efficacy on restrictive and repetitive behaviors in combination with behavioral interventions. Stimulants, and to a lesser extent atomoxetine, are effective in reducing hyperactivity, inattention and impulsivity also in comorbid ASD-ADHD, although with somewhat lower efficacy and greater incidence of side effects compared to idiopathic ADHD. Clonidine and guanfacine display some efficacy on hyperactivity and stereotypic behaviors. For several other drugs, case reports and open-label studies suggest possible efficacy, but no randomized controlled trial has yet been performed. Research in the pediatric psychopharmacology of ASD is still faced with at least two major hurdles: (a) Great interindividual variability in clinical response and side effect sensitivity is observed in the ASD population. This low level of predictability would benefit from symptom-specific treatment algorithms and from biomarkers to support drug choice; (b) To this date, no psychoactive drug appears to directly ameliorate core autism symptoms, although some indirect improvement has been reported with several drugs, once the comorbid target symptom is abated.
Effect of prednisolone on language function in children with autistic spectrum disorder: a randomized clinical trial
2021, Jornal de Pediatria
Citation Excerpt :
Nevertheless, patients are often treated with drugs that aim to alleviate associated behavioral symptoms, such as irritability and aggression, and comorbid disorders such as attention deficit/hyperactivity, nervous tics/Tourette's syndrome, anxiety, and depression.5,6 Studies have also evaluated interventions addressing the central manifestations of ASD with the administration of drugs7–10 and even stem cell use,11 whose preliminary results have not shown unequivocal efficacy. Corticosteroids have emerged as a therapeutic possibility in ASD from isolated case reports describing significant improvement in language and behavioral symptoms after steroid administration for another purpose.12,13
To describe the effect of prednisolone on language in children with autism spectrum disorder. This study is based upon two hypotheses: autism etiology may be closely related to neuroinflammation; and, an effective treatment should restore the individual's language skills.
This is a prospective, double-blinded, randomized, placebo-controlled clinical trial, carried out in a federal university hospital. The initial patient sample consisted of 40 subjects, which were randomized into two parallel groups. Inclusion criteria were: male gender, 3–7 years of age, and meeting the Diagnostic and Statistical Manual of Mental Disorders – 4th edition (DSM-IV) diagnostic criteria. The final sample consisted of 38 patients, of whom 20 were randomized to the placebo group and 18 to the active group. The latter received prednisolone for 24 weeks, at an initial dose of 1 mg/kg/day and a tapering dose from the ninth week onward. Language was measured on four occasions over a 12-month period by applying two Brazilian tools: the Language Development Assessment (ADL) and the Child Language Test in Phonology, Vocabulary, Fluency, and Pragmatics (ABFW).
The side effects were mild: two patients had hypertension, five had hyperglycemia, and two had varicella. Prednisolone increased the global ADL score in children younger than 5 years of age who had developmental regression (p = 0.0057). The ABFW's total of communicative acts also responded favorably in those participants with regression (p = 0.054). The ABFW's total of vocal acts showed the most significant results, especially in children younger than 5 years (p = 0.004, power = 0.913).
The benefit of prednisolone for language scores was more evident in participants who were younger than five years, with a history of developmental regression, but the trial's low dose may have limited this benefit. The observed side effects do not contraindicate corticosteroid use in autism.

View all citing articles on Scopus

View full text

Double-blind, placebo-controlled trial of risperidone plus topiramate in children with autistic disorder

Abstract

Background

Method

Results

Conclusion

Introduction

Section snippets

Methods

Results

Discussion

Acknowledgments

Prog Neuropsychopharmacol Biol Psychiatry

Brain Dev

Med Hypotheses

J Pediatr Health Care

Cyproheptadine in the treatment of autistic disorder: a double-blind and placebo controlled trial

J Clin Pharm Ther

A double-blind placebo controlled trial of piracetam added to risperidone in patients with autistic disorder

Child Psychiatry Hum Dev

The aberrant behavior checklist: a behavior rating scale for assessment of treatment effects

Am J Ment Defic

Diagnostic and statistical manual of mental disorders

Divalproex versus placebo for the prevention of irritability associated with fluoxetine treatment in autism spectrum disorder

J Clin Psychopharmacol

Lamotrigine therapy for autistic disorder: A randomized, double-blind, placebo controlled trial

J Autism Dev Disord

Topiramate in the management of bipolar disorder

Child Adolesc Psychopharmacol News

Extrapyramidal symptoms rating scale (abstract)

Can J Neurol Sci

Targeting the glutamate system in the treatment of autistic spectrum disorders

Curr Psychiatry Rep